Heterocycles in asymmetric synthesis. Part 2. Efficient asymmetric approaches to heteroyohimbine, yohimbine and related alkaloids

Abstract

Asymmetric syntheses of heteroyohimbine, yohimbine, and related alkaloids are reported. The piperidine derivative ethyl (–)-(3-acetyl-1-benzylpiperidin-4-yl)acetate (–)-2, which was obtained by an asymmetric intramolecular Michael reaction of the acyclic compound ethyl 5-[benzyl-(3-oxobutyl)-amino]pent-2-enoate 1, was stereoselectively converted into the (–)-lactone methyl (1S,4aR,8aR)-3,4,4a,5,6,7,8,8a-octahydro-1 -methyl-3-oxo-1H-pyrano[3,4-c]pyridine-7-carboxylate (–)-7 and (+)-olefin methyl [(R)-3-(Z)-ethylidene-1-methoxycarbonylpiperidin-4-yl]acetate 15. The (–)-lactone (–)-7 was transformed into (–)-ajmalicine 3 in 5 steps. The (+)-olefin (+)-15 is the precursor in a published route to (–)-tetrahydroaistonine. Tne (–)-piperidine (–)-2 was also converted into the αβ-unsaturated ketone t-butyl (4aR,8aR)-(–)-1,2,3,4,4a,5,6,8a-octahydro-6-oxoisoquinoline-2-carboxylate (–)-30 in 6 steps. Stsreoselective introduction of the methoxycarbonyl group into this last compound, followed by stereoselective reduction of the ketone moiety with L-Selectride, afforded the D/E-ring system of (+)-yohimbine. This can be converted into yohimbine by following the established sequence. The conversion of the (–)-piperidine derivative (–)-2 ethyl [(4R,5R)-5-ethyl-2-oxopiperidin-4-yl]acetate (+)-21 for the synthesis of (–)-emetine 23 was also accomplished.